CD26 is a widely distributed 110 kDa cell surface glycoprotein, initially defined as a T-cell activation antigen (Fox et al. (1984) J. Immunol. 133, 1250-1256, Fleischer (1987) J. Immunol. 138, 1346-1350, and Morimoto et al. (1989) J. Immunol. 143, 3430-3439). This molecule has been shown to have dipeptidyl peptidase IV (DPPIV; EC3.4.14.5) activity in its extracellular domain, and wide tissue distribution (Hegen et al. (1990) J. Immunol. 144, 2908-2914 and Ulmer et al. (1990) J. Immunol. 31, 429-435; WO 2007/014169 A2). CD26 has multiple functions in human T-cell physiology. For instance, evidence suggests that CD26 can deliver a costimulatory signal for T-cell activation (Morimoto et al. (1994) Immunologist 2: 4-7 and Fleischer (1994) Immunol. Today 15:180-184). Further, CD26 has been identified as the ADA binding protein, and the CD26/ADA complex may play a key role in regulating immune system function (Dong et al. (1996) J Immunol. 156(4):1349-55, Kameoka et al. (1993) Science. 261(5120):466-9, and Morrison et al. (1993) J Exp Med. 177(4):1135-43). A functional association between CD26 and the cellular protein topoisomerase II a has also been reported (Aytac et al. (2003) British Journal of Cancer 88:455-462). Anti-CD26 antibodies are e.g. known from WO 2007/014169 A2.
Haematopoietic stem cell transplantation (HSCT) represents an important therapy for many haematological and numerous epithelial malignancies, as well as for a considerable number of non-malignant diseases (Ferrara et al., 2009, Lancet.; 373: 1550-1561; Sun et al., 2007, Transl. Res.; 150: 197-214). Graft-versus-host disease (GvHD) is a major complication of allogeneic haematopoietic stem cell transplantation (HSCT), and therefore limits the use of these important therapies.
There are two major types of haematopoietic cell transplantation: autologous and allogeneic. Autologous transplantation involves isolation of haematopoietic stem cells (HSC) from a patient, storage of the stem cells, medical treatment of the patient that destroys stem cells remaining in the body, and return of the patient's own stored stem cells to his body. Autologous transplants have the advantage of a lower risk of graft rejection, infection and other correlated diseases. Allogeneic transplantation involves two persons: one is the healthy donor and one is the patient or recipient. Allogeneic HSC donors must have a tissue (HLA human leukocyte antigens) type that matches the recipient and, in addition, the recipient requires immunosuppressive medications. There are three possible sources of haematopoietic stem cells for transplantation: the Bone Marrow (BM), the Peripheral Blood (PB) and the Umbilical Cord Blood (UCB).
The development of novel strategies has helped to expand the indications for allogeneic HSCT over the last several years (Sun et al., 2007, supra). Improvements in infectious prophylaxis, immunosuppressive medications, supportive care and DNA-based tissue typing have also contributed to improved outcomes after allogeneic HSCT (Ferrara et al., 2009, supra). For these reasons, the number of allogeneic haematopoietic cell transplantations continues to increase. However, graft-versus-host disease (GvHD) remains a major complication of allogeneic HSCT.
GvHD occurs when donor T cells identify genetically defined proteins on host cells as not-self and mount an immune response in order to destroy them (Ferrara et al., 2009, supra). Depending on the time at which it occurs after HSCT, GvHD can be either acute or chronic. Acute GvHD (aGvHD) is responsible for 15% to 40% of mortality and is the major cause of morbidity after allogeneic HCT, while chronic GvHD (cGvHD) occurs up to 50% of patients who survive three months after HCT (Sun et al., 2007, Transl. Res.; 150: 197-214).
Acute Graft-versus-Host Disease generally occurs after allogeneic HSCT as reaction of donor immune cells against host tissues. The three main tissues affected by acute GvHD are the skin, liver, and gastrointestinal tract. Clinically, the diagnosis is suspected when a recipient of HSCT develops any or all of the following signs or symptoms: dermatitis (skin rash), cutaneous blisters, crampy abdominal pain with or without diarrhea, persistent nausea and vomiting, hepatitis (with elevation of bilirubin and/or liver enzymes). Symptoms most frequently start with donor engraftment, before day 100 after the HSCT, but may also occur late. Acute GvHD is a clinical diagnosis confirmed by histological evidences.
Acute GvHD can be staged by the number and extent of organ involvement. The current staging system is derived from Glucksberg first aGvHD classification in 1974 (Glucksberg et al., 1974, Transplantation; 18:4 295-304). Recent data support the use of the grading system, since it is able to subdivide patients into risk categories for complications and mortality. In this system, patients are divided into one of four grades (I-IV) depending on the degree or stage of involvement in three organs. The skin is staged with percent body surface involved, the liver is staged with degree of bilirubin elevation, and the gastrointestinal tract is staged with amount of diarrhea. Using these criteria, a single grade is assigned to each patient (Jacobsohn et al., 2007, Orphanet J. of Rare Diseases; 2:35).
Various clinical manifestations of GvHD are known. The earliest and most common manifestation is skin GvHD. This is essentially a maculopapular rash that can begin anywhere in the body but often start with palm and sole involvement. The patient may complain of pruritus or tenderness in affected areas. In severe cases, blisters may occur. The gastrointestinal manifestations include diarrhea, which may become bloody, cramping, nausea, vomiting and failure to thrive. Furthermore, jaundice from hyperbilirubinemia is the hallmark of liver GvHD (Jacobsohn et al., 2007, supra), although a hepatitic variant of GvHD with a rise in liver enzymes like an acute viral hepatitis, has been recognized (Akpek et al., 2002, Blood; 100: 3903-3907). Even if methylprednisolone is not registered in any European Countries for this indication, it is considered current standard of care in first line treatment of acute GvHD.
First line treatment of acute GvHD, with methylprednisolone 2 mg/kg/day is effective in over 50% of patients, but produces durable responses only in ⅓ of the patients. Non responders are offered second line therapy, which is based on combinations of immunosuppressive agents not registered in this indication. Second line therapy is largely unsatisfactory with one year survival of 30% in most large clinical trials. None of these strategies has achieved the level of success required to become standard of care. After 30 years of transplant experience steroid refractory acute GvHD (aGvHD), remains largely an untreatable disease. It has to be emphasized that aGvHD patients resistant to steroid therapy have very limited therapeutic options and that there are no currently authorized treatments for this clinical situation. This condition is life-threatening in particular due to the increased mortality in this patient population, particularly secondary to infection.
Any clinically relevant result in this patient population would be of significant benefit as it would offer a clinically relevant advantage for steroid resistant aGvHD patients.
Moreover, approaches for facilitating engraftment after haematopoietic stem cell transplantation, will be useful. Engraftment is the process in which the transplanted stem cells find their way to the bone marrow spaces in the centre of the large bones of the body. Only then can the transplanted stem cells begin to produce new blood cells. Experts are not completely certain how this process happens but it is generally acknowledged that this is a long process: it takes approximately two to four weeks after the bone marrow is infused for engraftment to occur. Until the blood stem cells engraft, the patient will be at risk of developing an infection. This is because the transplanted patient has been normally subjected to radiation and/or chemotherapy, whose result is the destruction of the white blood cells in the patient's body. While waiting for the engraftment, a transplanted patient could suffer of serious complication due to an infection (caused by bacteria, virus or fungus), which is one of the main cause of transplant related mortality after Bone Marrow Transplantation (BMT). Accordingly, there is a need in the art for an agent able to improve engraftment. Such an agent will be of significant value for BM transplanted patients. If homing and engraftment can be enhanced, the time to recovery of hematopoietic lineages can be reduced resulting in less engraftment failures and better overall survival, especially in UCB transplantation (Broxmeyer, H. E. (2006). Umbilical Cord Blood Stem Cells: Collection, Processing, and Transplantation. Blood Banking and Transfusion Medicine: Basic Principles and Practice. C. D. Hillyer et al., Churchill Livingston, an imprint of Elsevier, Inc.: 823-832; Lewis, 2002, Intern Med J 32(12): 601-9).
Aplastic anemia is a type of anemia, wherein bone marrow fails to produce sufficient amounts of blood cells for replenishing blood cells. In particular, a congenital and an acquired form of aplastic anemia may exist. Acquired aplastic anemia (AA) is a rare bone marrow failure state characterized by marrow hypocellularity and low peripheral blood cell counts [Young N S, Maciejewski J P. The pathophysiology of acquired aplastic anemia. N Eng J Med 1997, 336:1365-1372]. The evidence of an autoimmune pathogenesis is mostly indirect and the characterization of the underlying immune response is incomplete mainly due to technical difficulties resulting from the disease-specific hypocellularity. Acquired Aplastic anemia is thought to be an immunomediated disease, and current standard non transplant therapy is anti-thymocyte globulin (ATG) plus cyclosporin A (CsA). Failures include patients not responding to first line (30%) and patients relapsing after a first response (30%), such that event free survival does not exceed 30-40% (Bacigalupo A., Passweg J., 2009, Hematol Oncol Clin North Am. 23: 159-70).
Untreated aplastic anemia may lead to death, in some cases even within a short period of merely several months. Current treatments of aplastic anemia encompass for example bone marrow transplantation or immunosuppressive drug therapies. Immunosuppressive drug therapies fail however in a significant number of cases and bone marrow transplantation is not possible in absence of an appropriate donor. Thus, there is also a need in the art to provide alternative agent(s) for treating aplastic anemia, which preferably may be effective for treating patients which are non-responsive to at least one other therapy.